The nucleus basalis of the basal forebrain gives rise to the cholinergic innervation of the cerebral cortex and the amygdala. This projection provides the largest extra-thalamic neuromodulatory input to the cerebral cortex and can be considered as a major component of the Ascending Reticular Activating System. Behavioral and physiological experiments have implicated this pathway in the regulation of memory and attention. Age-related changes in cortical cholinergic innervation may provide an important substrate for the memory disturbances associated with physiological aging. The severe and early degeneration of this pathway in patients with Alzheimer's disease may account for some of the cognitive deficits experienced by these patients and holds important clues to the causes of this disease. The organization of this cholinergic pathway along the information-processing systems of the human brain has been the principal research focus of this laboratory for the past 15 years. In this competitive renewal, we propose to extend our work into two novel directions. First, we propose to delineate the organization of the m2 receptor subtype in the primate cerebral cortex and the nucleus basalis. Secondly, we propose to initiate electron microscopic studies to elucidate the synaptic organization of cholinergic circuitry and cholinergic-monoaminergic interactions. We also propose, to continue ongoing work on the cytochemical signatures of a special group of acetylcholinesterase-rich cortical neurons. These neurons are more numerous in the human brain than in any other species that we have studied, including monkeys and baboons. The enzymatic profile of these putatively cholinoceptive neurons does not become fully established in the human brain until adolescence and shows no involutional changes even in advanced senescence. The distribution and density of these neurons will be quantitated and correlated with cognitive performance in specimens from neuropsychologically-investigated subjects. The methodology will involve light- and electron-microscopy, enzyme histochemistry, immunocytochemistry for single and double labeling, quantitative stereological cell counting, and computerized densitometry. Experiments will be conducted in Macaca fascicularis, surgically removed cortical tissue from epileptic patients, and post-mortem specimens from neurologically normal individuals and patients with Alzheimer's disease.